Organisation and evolution of the major histocompatibility complex class I genes in cetaceans.

A quarter of marine mammals are at risk of extinction, with disease and poor habitat quality contributing to population decline. Investigation of the Major Histocompatibility Complex (MHC) provides insight into species' capacity to respond to immune and environmental challenges. The eighteen available cetacean chromosome level genomes were used to annotate MHC Class I loci, and to reconstruct the phylogenetic relationship of the described loci. The highest number of loci was observed in the striped dolphin (Stenella coeruleoalba), while the least was observed in the pygmy sperm whale (Kogia breviceps) and rough toothed dolphin (Steno bredanensis). Of the species studied, Mysticetes had the most pseudogenes. Evolutionarily, MHC Class I diverged before the speciation of cetaceans. Yet, locus one was genomically and phylogenetically similar in many species, persisting over evolutionary time. This characterisation of MHC Class I in cetaceans lays the groundwork for future population genetics and MHC expression studies.

Transmissible cancers, the genomes that don't melt down.

Evolutionary theory predicts that accumulation of deleterious mutations in asexually reproducing organisms should lead to genomic decay. Clonally reproducing cell lines, i.e., transmissible cancers, when cells are transmitted as allografts/xenografts, break these rules, and survive for centuries and millennia. The currently known 11 transmissible cancer lineages occur in dogs (Canine Venereal Tumour Disease, CTVT), in Tasmanian devils (Devil Facial Tumour Diseases, DFT 1 and DFT2) and in bivalves (bivalve transmissible neoplasia, BTN). Despite the mutation loads of these cell lines being much higher than observed in human cancers, they have not been eliminated in space and time. Here we provide potential explanations how these fascinating cell lines may have overcome the fitness decline due to the progressive accumulation of deleterious mutations and propose that the high mutation load may carry an indirect positive fitness outcome. We offer ideas on how these host-pathogen systems could be used to answer outstanding questions in evolutionary biology. The recent studies on the evolution of these clonal pathogens reveal key mechanistic insight into transmissible cancer genomes, information that is essential for future studies investigating how these contagious cancer cell lines can repeatedly evade immune recognition, evolve, and survive in the landscape of highly diverse hosts.

[Evolution of cancer resistance in the animal kingdom]. / Évolution de la résistance au cancer dans le monde animal.

Cancer is an inevitable collateral problem inherent in the evolution of multicellular organisms, which appeared at the end of the Precambrian. Faced to this constraint, a range of diverse anticancer defenses has evolved across the animal kingdom. Today, investigating how animal organisms, especially those of large size and long lifespan, manage cancer-related issues has both fundamental and applied outcomes, as it could inspire strategies for preventing or treating human cancers. In this article, we begin by presenting the conceptual framework for understanding evolutionary theories regarding the development of anti-cancer defenses. We then present a number of examples that have been extensively studied in recent years, including naked mole rats, elephants, whales, placozoa, xenarthras (such as sloths, armadillos and anteaters) and bats. The contributions of comparative genomics to understanding evolutionary convergences are also discussed. Finally, we emphasize that natural selection has also favored anti-cancer adaptations aimed at avoiding mutagenic environments, for example by maximizing immediate reproductive efforts in the event of cancer. Exploring these adaptive solutions holds promise for identifying novel approaches to improve human health.

Title: Évolution de la résistance au cancer dans le monde animal. Abstract: Le cancer est un dommage collatéral inévitable inhérent à l'évolution des organismes multicellulaires, apparus à la fin du Précambrien. L'exploration de la manière dont les animaux, en particulier ceux de grande taille et de longue durée de vie, font face au cancer, comporte des enjeux à la fois fondamentaux et appliqués. Dans cet article, nous commençons par présenter le cadre conceptuel nécessaire pour comprendre les théories qui traitent de l'évolution des défenses anti-cancéreuses. Nous présentons ensuite un certain nombre d'exemples, notamment les rats-taupes nus, les éléphants, les baleines, les xénarthres (paresseux, tatous et fourmiliers), les chauves-souris et les placozoaires1. Les contributions de la génomique comparative à la compréhension des convergences évolutives sont également abordées. Enfin, nous indiquons que la sélection naturelle a également favorisé des adaptations visant à éviter les zones mutagènes, par exemple, ou à maximiser l'effort de reproduction immédiat en cas de cancer. L'exploration de ces solutions, intéressante conceptuellement, pourrait aussi permettre d'envisager de nouvelles approches thérapeutiques pour la santé humaine.

Complex associations between cancer progression and immune gene expression reveals early influence of transmissible cancer on Tasmanian devils.

The world's largest extant carnivorous marsupial, the Tasmanian devil, is challenged by Devil Facial Tumor Disease (DFTD), a fatal, clonally transmitted cancer. In two decades, DFTD has spread across 95% of the species distributional range. A previous study has shown that factors such as season, geographic location, and infection with DFTD can impact the expression of immune genes in Tasmanian devils. To date, no study has investigated within-individual immune gene expression changes prior to and throughout the course of DFTD infection. To explore possible changes in immune response, we investigated four locations across Tasmania that differed in DFTD exposure history, ranging between 2 and >30 years. Our study demonstrated considerable complexity in the immune responses to DFTD. The same factors (sex, age, season, location and DFTD infection) affected immune gene expression both across and within devils, although seasonal and location specific variations were diminished in DFTD affected devils. We also found that expression of both adaptive and innate immune genes starts to alter early in DFTD infection and continues to change as DFTD progresses. A novel finding was that the lower expression of immune genes MHC-II, NKG2D and CD8 may predict susceptibility to earlier DFTD infection. A case study of a single devil with regressed tumor showed opposite/contrasting immune gene expression patterns compared to the general trends observed across devils with DFTD infection. Our study highlights the complexity of DFTD's interactions with the host immune system and the need for long-term studies to fully understand how DFTD alters the evolutionary trajectory of devil immunity.

In vitro competition between two transmissible cancers and potential implications for their host, the Tasmanian devil.

Since the emergence of a transmissible cancer, devil facial tumour disease (DFT1), in the 1980s, wild Tasmanian devil populations have been in decline. In 2016, a second, independently evolved transmissible cancer (DFT2) was discovered raising concerns for survival of the host species. Here, we applied experimental and modelling frameworks to examine competition dynamics between the two transmissible cancers in vitro. Using representative cell lines for DFT1 and DFT2, we have found that in monoculture, DFT2 grows twice as fast as DFT1 but reaches lower maximum cell densities. Using co-cultures, we demonstrate that DFT2 outcompetes DFT1: the number of DFT1 cells decreasing over time, never reaching exponential growth. This phenomenon could not be replicated when cells were grown separated by a semi-permeable membrane, consistent with exertion of mechanical stress on DFT1 cells by DFT2. A logistic model and a Lotka-Volterra competition model were used to interrogate monoculture and co-culture growth curves, respectively, suggesting DFT2 is a better competitor than DFT1, but also showing that competition outcomes might depend on the initial number of cells, at least in the laboratory. We provide theories how the in vitro results could be translated to observations in the wild and propose that these results may indicate that although DFT2 is currently in a smaller geographic area than DFT1, it could have the potential to outcompete DFT1. Furthermore, we provide a framework for improving the parameterization of epidemiological models applied to these cancer lineages, which will inform future disease management.

Small extracellular vesicles from surviving cancer cells as multiparametric monitoring tools of measurable residual disease and therapeutic efficiency.

Although conventional anti-cancer therapies remove most cells of the tumor mass, small surviving populations may evolve adaptive resistance strategies, which lead to treatment failure. The size of the resistant population initially may not reach the threshold of clinical detection (designated as measurable residual disease/MRD) thus, its investigation requires highly sensitive and specific methods. Here, we discuss that the specific molecular fingerprint of tumor-derived small extracellular vesicles (sEVs) is suitable for longitudinal monitoring of MRD. Furthermore, we present a concept that exploiting the multiparametric nature of sEVs may help early detection of recurrence and the design of dynamic, evolution-adjusted treatments.

Behavioural ecology meets oncology: quantifying the recovery of animal behaviour to a transient exposure to a cancer risk factor.

Wildlife is increasingly exposed to sublethal transient cancer risk factors, including mutagenic substances, which activates their anti-cancer defences, promotes tumourigenesis, and may negatively impact populations. Little is known about how exposure to cancer risk factors impacts the behaviour of wildlife. Here, we investigated the effects of a sublethal, short-term exposure to a carcinogen at environmentally relevant concentrations on the activity patterns of wild Girardia tigrina planaria during a two-phase experiment, consisting of a 7-day exposure to cadmium period followed by a 7-day recovery period. To comprehensively explore the effects of the exposure on activity patterns, we employed the double hierarchical generalized linear model framework which explicitly models residual intraindividual variability in addition to the mean and variance of the population. We found that exposed planaria were less active compared to unexposed individuals and were able to recover to pre-exposure activity levels albeit with a reduced variance in activity at the start of the recovery phase. Planaria showing high activity levels were less predictable with larger daily activity variations and higher residual variance. Thus, the shift in behavioural variability induced by an exposure to a cancer risk factor can be quantified using advanced tools from the field of behavioural ecology. This is required to understand how tumourous processes affect the ecology of species.

Manganese Exacerbates Seasonal Health Declines in a Suicidally Breeding Mammal.

Reproductive costs must be balanced with survival to maximize lifetime reproductive rates; however, some organisms invest in a single, suicidal bout of breeding known as semelparity. The northern quoll (Dasyurus hallucatus) is an endangered marsupial in which males, but not females, are semelparous. Northern quolls living near mining sites on Groote Eylandt, Northern Territory, Australia, accumulate manganese (Mn) in their brains, testes, and hair, and elevated Mn impacts motor performance. Whether Mn is associated with other health declines is yet unknown. In the present study we show that male and female northern quolls with higher Mn accumulation had a 20% reduction in immune function and a trend toward reduced cortisol concentrations in hair. The telomere lengths of male quolls did not change pre- to postbreeding, but those with higher Mn levels had longer telomeres; in contrast, the telomeres of females shortened during the breeding season but recovered between the first year and second year of breeding. In addition, the telomeres of quolls that were recaptured declined at significantly higher rates in quolls with higher Mn between prebreeding, breeding, and/or postbreeding seasons. Future research should determine whether changes in cortisol, immune function, or telomere length affect reproductive output or survival-particularly for semelparous males. Environ Toxicol Chem 2024;43:74-86. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

The effect of mitochondrial recombination on fertilization success in blue mussels.

The presence of doubly uniparental inheritance (DUI) in bivalves represents a unique mode of mitochondrial transmission, whereby paternal (male-transmitted M-type) and maternal (female-transmitted F-type) haplotypes are transmitted to offspring separately. Male embryos retain both haplotypes, but the M-type is selectively removed from females. Due to the presence of heteroplasmy in males, mtDNA can recombine resulting in a 'masculinized' haplotype referred to as Mf-type. While mtDNA recombination is usually rare, it has been recorded in multiple mussel species across the Northern Hemisphere. Given that mitochondria are the powerhouse of the cell, different mtDNA haplotypes may have different selective advantages under diverse environmental conditions. This may be particularly important for sperm fitness and fertilization success. In this study we aimed to i) determine the presence, prevalence of the Mf-type in Australian blue mussels (Mytilus sp.) and ii) investigate the effect of Mf-mtDNA on sperm performance (a fitness correlate). We found a high prevalence of recombined mtDNA (≈35 %) located within the control region of the mitochondrial genome, which occurred only in specimens that contained Southern Hemisphere mtDNA. The presence of two female mitotypes were identified in the studied mussels, one likely originating from the Northern Hemisphere, and the other either representing the endemic M. planulatus species or introduced genotypes from the Southern Hemisphere. Despite having recombination events present in a third of the studied population, analysis of sperm performance indicated no difference in fertilization success related to mitotype.

The impact of food availability on tumorigenesis is evolutionarily conserved.

The inability to control cell proliferation results in the formation of tumors in many multicellular lineages. Nonetheless, little is known about the extent of conservation of the biological traits and ecological factors that promote or inhibit tumorigenesis across the metazoan tree. Particularly, changes in food availability have been linked to increased cancer incidence in humans, as an outcome of evolutionary mismatch. Here, we apply evolutionary oncology principles to test whether food availability, regardless of the multicellular lineage considered, has an impact on tumorigenesis. We used two phylogenetically unrelated model systems, the cnidarian Hydra oligactis and the fish Danio rerio, to investigate the impact of resource availability on tumor occurrence and progression. Individuals from healthy and tumor-prone lines were placed on four diets that differed in feeding frequency and quantity. For both models, frequent overfeeding favored tumor emergence, while lean diets appeared more protective. In terms of tumor progression, high food availability promoted it, whereas low resources controlled it, but without having a curative effect. We discuss our results in light of current ideas about the possible conservation of basic processes governing cancer in metazoans (including ancestral life history trade-offs at the cell level) and in the framework of evolutionary medicine.

Cancer hygiene hypothesis: A test from wild captive mammals.

The hygiene hypothesis, according to which the recent reduction of exposure to infectious agents in the human species would be the origin of various diseases, including autoimmune diseases and cancer, has often been proposed but not properly tested on animals. Here, we evaluated the relevance of this hypothesis to cancer risk in mammals in an original way, namely by using information on zoo mammals. We predicted that a higher richness of parasitic cohorts in the species' natural habitat would result in a greater occurrence of evolutionary mismatch due to the reduction of parasites in captive conditions. This, in turn, could contribute to an increased risk of developing lethal cancers. Using a comparative analysis of 112 mammalian species, we explored the potential relationship between cancer risk and parasite species richness using generalized phylogenetic least squares regressions to relate parasite species richness to cancer risk data. We found no strong evidence that parasite species richness increased cancer risk in zoo mammals for any of the parasite groups we tested. Without constituting definitive proof of the irrelevance of the hygienic hypothesis, our comparative study using zoo mammals does not support it, at least with respect to cancer risks.

The tumour is in the detail: Local phylogenetic, population and epidemiological dynamics of a transmissible cancer in Tasmanian devils.

Infectious diseases are a major threat for biodiversity conservation and can exert strong influence on wildlife population dynamics. Understanding the mechanisms driving infection rates and epidemic outcomes requires empirical data on the evolutionary trajectory of pathogens and host selective processes. Phylodynamics is a robust framework to understand the interaction of pathogen evolutionary processes with epidemiological dynamics, providing a powerful tool to evaluate disease control strategies. Tasmanian devils have been threatened by a fatal transmissible cancer, devil facial tumour disease (DFTD), for more than two decades. Here we employ a phylodynamic approach using tumour mitochondrial genomes to assess the role of tumour genetic diversity in epidemiological and population dynamics in a devil population subject to 12 years of intensive monitoring, since the beginning of the epidemic outbreak. DFTD molecular clock estimates of disease introduction mirrored observed estimates in the field, and DFTD genetic diversity was positively correlated with estimates of devil population size. However, prevalence and force of infection were the lowest when devil population size and tumour genetic diversity was the highest. This could be due to either differential virulence or transmissibility in tumour lineages or the development of host defence strategies against infection. Our results support the view that evolutionary processes and epidemiological trade-offs can drive host-pathogen coexistence, even when disease-induced mortality is extremely high. We highlight the importance of integrating pathogen and population evolutionary interactions to better understand long-term epidemic dynamics and evaluating disease control strategies.

The paradox of cooperation among selfish cancer cells.

It is traditionally assumed that during cancer development, tumor cells abort their initially cooperative behavior (i.e., cheat) in favor of evolutionary strategies designed solely to enhance their own fitness (i.e., a "selfish" life style) at the expense of that of the multicellular organism. However, the growth and progress of solid tumors can also involve cooperation among these presumed selfish cells (which, by definition, should be noncooperative) and with stromal cells. The ultimate and proximate reasons behind this paradox are not fully understood. Here, in the light of current theories on the evolution of cooperation, we discuss the possible evolutionary mechanisms that could explain the apparent cooperative behaviors among selfish malignant cells. In addition to the most classical explanations for cooperation in cancer and in general (by-product mutualism, kin selection, direct reciprocity, indirect reciprocity, network reciprocity, group selection), we propose the idea that "greenbeard" effects are relevant to explaining some cooperative behaviors in cancer. Also, we discuss the possibility that malignant cooperative cells express or co-opt cooperative traits normally expressed by healthy cells. We provide examples where considerations of these processes could help understand tumorigenesis and metastasis and argue that this framework provides novel insights into cancer biology and potential strategies for cancer prevention and treatment.

The effect of placentation type, litter size, lactation and gestation length on cancer risk in mammals.

Reproduction is a central activity for all living organisms but is also associated with a diversity of costs that are detrimental for survival. Until recently, the cost of cancer as a selective force has been poorly considered. Considering 191 mammal species, we found cancer mortality was more likely to be detected in species having large, rather than low, litter sizes and long lactation lengths regardless of the placentation types. However, increasing litter size and gestation length are not per se associated with an enhanced cancer mortality risk. Contrary to basic theoretical expectations, the species with the highest cancer mortality were not those with the most invasive (i.e. haemochorial) placentation, but those with a moderately invasive (i.e. endotheliochorial) one. Overall, these results suggest that (i) high reproductive efforts favour oncogenic processes' dynamics, presumably because of trade-offs between allocation in reproduction effort and anti-cancer defences, (ii) cancer defence mechanisms in animals are most often adjusted to align reproductive lifespan, and (iii) malignant cells co-opt existing molecular and physiological pathways for placentation, but species with the most invasive placentation have also selected for potent barriers against lethal cancers. This work suggests that the logic of Peto's paradox seems to be applicable to other traits that promote tumorigenesis.

Spontaneously occurring tumors in different wild-derived strains of hydra.

Hydras are freshwater cnidarians widely used as a biological model to study different questions such as senescence or phenotypic plasticity but also tumoral development. The spontaneous tumors found in these organisms have been so far described in two female lab strains domesticated years ago (Hydra oligactis and Pelmatohydra robusta) and the extent to which these tumors can be representative of tumors within the diversity of wild hydras is completely unknown. In this study, we examined individuals isolated from recently sampled wild strains of different sex and geographical origin, which have developed outgrowths looking like tumors. These tumefactions have common features with the tumors previously described in lab strains: are composed of an accumulation of abnormal cells, resulting in a similar enlargement of the tissue layers. However, we also found diversity within these new types of tumors. Indeed, not only females, but also males seem prone to form these tumors. Finally, the microbiota associated to these tumors is different from the one involved in the previous lineages exhibiting tumors. We found that tumorous individuals hosted yet undescribed Chlamydiales vacuoles. This study brings new insights into the understanding of tumor susceptibility and diversity in brown hydras from different origins.

No evidence that spice consumption is a cancer prevention mechanism in human populations.

Background: Why humans historically began to incorporate spices into their diets is still a matter of unresolved debate. For example, a recent study (Bromham et al. There is little evidence that spicy food in hot countries is an adaptation to reducing infection risk. Nat Hum Behav 2021;5:878-91.) did not support the most popular hypothesis that spice consumption was a practice favoured by selection in certain environments to reduce food poisoning, parasitic infections, and foodborne diseases. Methods: Because several spices are known to have anticancer effects, we explored the hypothesis that natural selection and/or cultural evolution may have favoured spice consumption as an adaptive prophylactic response to reduce the burden of cancer pathology. We used linear models to investigate the potential relationship between age-standardized gastrointestinal cancer rates and spice consumption in 36 countries. Results: Patterns of spice are not consistent with a cancer mitigation mechanism: the age-standardized rate of almost all gastrointestinal cancers was not related to spice consumption. Conclusions: Direction other than foodborne pathogens and cancers should be explored to understand the health reasons, if any, why our ancestors developed a taste for spices.

Effect of MHC and inbreeding on disassortative reproduction: A data revisit, extension and inclusion of fertilization in sand lizards.

The harmful effects of close inbreeding have been recognized for centuries and, with the rise of Mendelian genetics, was realized to be an effect of homozygosis. This historical background led to great interest in ways to quantify inbreeding, its depression effects on the phenotype and flow-on effects on mate choice and other aspects of behavioral ecology. The mechanisms and cues used to avoid inbreeding are varied and include major histocompatibility complex (MHC) molecules and the peptides they transport as predictors of the degree of genetic relatedness. Here, we revisit and complement data from a Swedish population of sand lizards (Lacerta agilis) showing signs of inbreeding depression to assess the effects of genetic relatedness on pair formation in the wild. Parental pairs were less similar at the MHC than expected under random mating but mated at random with respect to microsatellite relatedness. MHC clustered in groups of RFLP bands but no partner preference was observed with respect to partner MHC cluster genotype. Male MHC band patterns were unrelated to their fertilization success in clutches selected for analysis on the basis of showing mixed paternity. Thus, our data suggest that MHC plays a role in pre-copulatory, but not post-copulatory partner association, suggesting that MHC is not the driver of fertilization bias and gamete recognition in sand lizards.

Polyandry and non-random fertilisation maintain long-term genetic diversity in an isolated island population of adders (Vipera berus).

Conservation genetic theory suggests that small and isolated populations should be subject to reduced genetic diversity i.e., heterozygosity and allelic diversity. Our 34 years study of an isolated island population of adders (Vipera berus) in southern Sweden challenges this notion. Despite a lack of gene flow and a yearly mean estimated reproductive adult population size of only 65 adult adders (range 12-171), the population maintains high levels of heterozygosity and allelic diversity similar to that observed in two mainland populations. Even a 14-year major "bottleneck" i.e., a reduction in adult adder numbers, encompassing at least four adder generations, did not result in any reduction in the island adders' heterozygosity and allelic diversity. Female adders are polyandrous, and fertilisation is non-random, which our empirical data and modelling suggest are underpinning the maintenance of the population's high level of heterozygosity. Our empirical results and subsequent modelling suggest that the positive genetic effects of polyandry in combination with non-random fertilisation, often overlooked in conservation genetic analyses, deserve greater consideration when predicting long-term survival of small and isolated populations.

Transmissible cancer and longitudinal telomere dynamics in Tasmanian devils (Sarcophilus harrisii).

A plethora of intrinsic and environmental factors have been shown to influence the length of telomeres, the protector of chromosome ends. Despite the growing interest in infection-telomere interactions, there is very limited knowledge on how transmissible cancers influence telomere maintenance. An emblematic example of transmissible cancer occurs in the Tasmanian devil (Sarcophilus harrisii), whose populations have been dramatically reduced by infectious cancer cells. To investigate associations between telomere dynamics and the transmissible cancer, we used longitudinal data from a Tasmanian devil population that has been exposed to the disease for over 15 years. We detected substantial temporal variation in individual telomere length (TL), and a positive significant association between TL and age, as well as a marginally significant trend for devils with devil facial tumour disease (DFTD) having longer telomeres. A proportional hazard analysis yielded no significant effect of TL on the development of DFTD. Like previous studies, we show the complexity that TL dynamics may exhibit across the lifetime of organisms. Our work highlights the importance of long-term longitudinal sampling for understanding the effects of wildlife diseases on TL.